Multilayer composite material

ABSTRACT

The present invention relates to a multilayer composite material for the treatment of wounds and lesions and to a dressing comprising said multilayer material.

This application is a Continuation of co-pending application Ser. No.16/975,672, filed on Aug. 25, 2020, which is the National StageApplication under 35 U.S.C. § 371 of International Application No.PCT/IB2019/051534, filed on Feb. 26, 2019, which claims the benefitunder 35 U.S.C. § 119(a) to Italian Patent Application No.102018000021112, filed on Dec. 27, 2018 and Italian Patent ApplicationNo. 102018000003034, filed on Feb. 26, 2018, all of which are herebyexpressly incorporated by reference into the present application.

The present invention relates to a multilayer composite material for thetreatment of wounds and injuries.

The treatment of wounds and lesions of the skin, and, optionally, of theunderlying tissues, to obtain cicatrization and healing, preferably withminimal aesthetic and functional consequences for the subject involved,is still a deeply felt need, to which it is not always possible to givea satisfactory answer either in the field of personal care or inhospitals.

In particular, dressings are available in the form of gauzes,compresses, plasters or the like, impregnated or soaked in substanceshaving a healing action, possibly associated with antibacterials and/orantiseptics. Gauzes impregnated with fatty substances or hydrocolloids,for example, are known in the state of the art, which act in anon-specific way, or with substances having an actual healing andrepairing action, such as natural extracts or hyaluronic acid (HA). Thelatter in particular has been widely used for a long time in thetreatment of wounds, ulcers and skin lesions of various origins,superficial or deep, thanks to its well-known properties on theregeneration of tissues.

It has been found, however, that dressings comprising a supportingfabric, commonly used for the treatment of wounds and injuries, have thedisadvantage that they can adhere to the biological tissues of the woundbeing repaired until they are partially englobed by the same. It shouldbe considered, in fact, that supporting fabrics may be hydrophilic orhydrophobic in nature, depending on the type of dressing to be obtainedand the type of lesion to be treated; for example, for an exuding wound,an absorbent hydrophilic supporting fabric, such as a cotton gauze, ispreferred. Furthermore, in order to convey the appropriately formulatedhealing substance, they must have large pores, in which the cicatrizingcomposition is distributed; it is precisely the pore size thatfacilitates the colonization of the supporting material by the scartissue being formed. This involves, during the dressing-change phase,the removal of portions of the biological tissues present, in particularthose in the regeneration phase and the possible consequent reopening ofthe wound with prolongation of the healing process. Furthermore, itshould not be forgotten that this causes severe pain in the patient. Inparticular, in cases of wounds with exudate and/or in the presence ofbiological tissues undergoing necrotization (eschar), the removal ofparts of the biological tissue that have incorporated the dressingresults in severe complications of the healing process, which may leadto scar formation and increase the risk of infection of the site of theoriginal wound and the surrounding area.

A further important disadvantage of the known dressings is due to thefact that, as the healing substance is arranged on a single layer ofsupporting material, it is released in the lesion very rapidly, nothomogeneously and not constantly over time.

Furthermore, fabrics based on natural fibers, such as cotton, commonlyused in gauzes, can release debris/residues in the wound, which cancomplicate the healing process and/or be incorporated in thepost-healing biological tissues, with unpleasant aesthetic aspects.

For all of these reasons, the dressings currently available must bereplaced, at least ideally, every 6-8 hours, with consequent economiccosts and with the need for constant intervention by the subject who hassuffered a wound or injury and/or specialized personnel.

The applicant has now surprisingly found that the disadvantages listedabove can be overcome.

DESCRIPTION

An object of the present invention relates to a multilayer compositematerial (CM) comprising at least:

-   a) a three-dimensional matrix comprising at least:    -   a first layer i. and a second layer ii. of a fabric comprising,        or consisting of a polyester fiber, wherein said first layer i.        and said second layer ii. are superimposed and welded together        in at least two distinct and separate points, so as to define a        space S between the two layers i. and ii. and-   b) a composition comprising, or consisting of    -   at least one natural, semi-synthetic or synthetic polymer,        possibly mixed together;    -   possibly one or more pharmacologically and/or biologically        active substance, and    -   at least one excipient suitable for pharmaceutical use,-   wherein said composition b) is contained in at least a part of said    space S included between the layers i. and ii.

A further object of the present invention relates to a multilayercomposite material (CM) as defined above for use in the treatment of awound, abrasion, cut, ulcer, sore, burn, lesion or laceration of theskin in a subject, wherein said treatment comprises the application ofsaid multilayer composite material on the surface of the wound,abrasion, cut, ulcer, sore, burn, lesion or laceration of the skin and,possibly, of the underlying tissues.

The applicant has therefore surprisingly found that the disadvantageslisted above can be overcome by means of a multilayer composite materialwhose supporting structure is a three-dimensional matrix, consisting ofat least two layers of synthetic fabric, fixed together at regularintervals, to form a cage which contains a healing substance, preferablyhyaluronic acid, which is released homogenously, uniformly andconstantly over time.

The multilayer composite material, object of the present invention, isprovided with the following features:

-   -   it is soft, flexible, can be cut according to the site of        application and is therefore perfectly adaptable to the bed of        the wound;    -   it allows a uniform and homogeneous distribution of the        cicatrizing composition, preferably HA, and therefore a constant        release over time;    -   it remains firmly fixed on the wound;    -   it can be easily and painlessly removed, and without the        undesired removal of newly formed healing tissue;    -   it does not release debris/residues in the wound;    -   it can be sterilized with gamma or beta rays;    -   it can be replaced every 24, 48 or 72 hours.

The combination of these characteristics makes it effective in promotingthe healing of wounds on which it is applied and absolutely innovativecompared to what is currently available.

Unless otherwise indicated, within the scope of the present invention,the percentages and quantities of a component in a mixture should referto the weight of said component with respect to the total weight of themixture.

Unless otherwise specified, within the scope of the present invention,the indication that a composition “comprises” one or more components orsubstances means that other components or substances may be present inaddition to that, or those, specifically indicated.

Unless otherwise specified, within the scope of the present invention, arange of values indicated for an amount, for example the weight contentof a component, includes the lower limit and the upper limit of therange. For example, if the weight or volume content of a component A isindicated as “from X to Y”, wherein X and Y are numerical values, A canbe X or Y or any of the intermediate values.

In the context of the present invention, the term “multilayer compositematerial (CM)” indicates the combination of at least two layers (i. andii.) of fabric comprising at least one polyester and of the compositionb) which is contained inside the space between said layers i. and ii.

It is understood that said multilayer composite material (CM) mayconstitute, or form part of, a dressing suitable for the treatment of awound, injury, laceration, ulcer, burn and the like, which is suitablefor protecting and promoting the healing of said wound, injury,laceration, ulcer, burn and the like. In particular, the multilayercomposite material (CM) of the present invention can be used in thepreparation of an advanced dressing, i.e. comprising coating materialswith biocompatibility characteristics and at least one active material,i.e. capable of playing an active role in tissue repair and, at times,modifying the cellular matrix.

By way of non-limiting example, the composite material (CM) or thedressing comprising said material according to the present invention canbe in the form of a gauze, a compress, a plaster or the like. Thecicatrizing composition b) contained in the three-dimensional matrix a)can be in different pharmaceutical forms also according to thecomponent/s forming said composition. Creams, ointments, emulsions, gelsand hydrogels, powders, water-based and non-water-based solutions,suspensions, etc., should therefore be considered as being possiblepharmaceutical forms of the composition b).

The multilayer composite material (CM) according to the presentinvention can be used in human subjects or for veterinary use, forexample, but without limitation, in pets such as dogs or cats, or inother mammals. The multilayer composite material (CM) according to thepresent invention is preferably for use in human beings.

In the context of the present invention, “wound”, “injury”,“laceration”, “ulcer”, “burn” and similar terms, refer to anyinterruption of the integrity of the skin such as, without limitation,those due to a traumatic event, surgery, pathologies or disorders ofvarious kinds (e.g. diabetic or vascular ulcers), to sores, for examplefrom decubitus, to a tear or bruise, with or without the production ofexudates and/or the effusion of body fluids such as blood.

In the composition b) of the multilayer composite material (CM)according to the present invention, comprising or consisting of

-   -   at least one natural, semi-synthetic or synthetic polymer,        possibly mixed together;    -   possibly one or more pharmacologically and/or biologically        active substances, and    -   at least one excipient suitable for pharmaceutical use,        wherein said composition b) is contained in at least a part of        said space S included between the layers i. and ii.,        the natural or semi-synthetic polymers are preferably selected        from polysaccharides, proteins, polypeptides or polynucleotides;        the synthetic polymers are preferably selected from polyacrylic        acid; polyacrylates and relative derivatives, such as pHEMA        [poly-2-hydroxyethyl-methacrylate]; polyaspartamide;        poly(ethyleneglycol) (PEG); polyvinyl-pyrrolidone; polylactic        acid, poly(lactic-glycolic) acid such as poly-lactic-co-glycolic        acid (PLGA), polyglycolic acid (PGA), polycaprolactone;        polyanhydrides; polyorthoesters; polyphosphoesters;        polyphosphazenes; polycyanoacrylic derivatives;        poly(N-isopropylacrylamide); polylysine; polyhistidine;        polyamidoamine; polyglutamic acid; polysiloxanes; polyurethanes;        polytetrafluoroethylene (PTFE); even more preferably, the        synthetic polymers are polyurethanes.

The polysaccharides are preferably selected from:

-   -   glycosaminoglycans: more preferably hyaluronic acid and/or        derivatives thereof such as salts, esters, amides and sulfated        hyaluronic acid; hybrid complexes of high- and        low-molecular-weight hyaluronic acid (as described in        WO2012/032151); chondroitin, chondroitin sulfate, dermatan        sulfate, keratansulfate, heparan sulfate, heparin and        heparinoids;    -   chitin, chitosan and its derivatives: more preferably chitosan        derivatized with lactose (as described in WO2007/135116 and        WO2017/211776);    -   pectin or pectinic acid;    -   galactans: more preferably agar and agarose;    -   alginates: more preferably alginic acid;    -   glucans: more preferably dextran, dextrin, trehalose, maltose,        starch, cellulose and its derivatives, and even more preferably        hydroxyethylcellulose, carboxymethylcellulose,        hydroxymethylcellulose and cellulose acetate;    -   natural gums, xanthan, gellan;    -   fructans: preferably inulin;    -   polymannans;    -   carrageenan.

The proteins or polypeptides are preferably selected from:

-   -   collagen, co-precipitates of collagen and glycosaminoglycans,        gelatin, elastin, fibrin, fibrinogen, keratin, silk, silk        fibroin alone or in combination with sericin, silk sericin.

The most preferred polysaccharides are the sodium salt of hyaluronicacid with a molecular weight ranging from 150 to 2,000 kDa, theabove-mentioned hybrid complexes in which the high-molecular-weighthyaluronic acid ranges from 1,100 to 1,400 kDa and thelow-molecular-weight hyaluronic acid ranges from 80 to 100 kDa, andchitosan derivatized with lactose, whereas even more preferred proteinsare collagen and silk proteins.

The pharmacologically and/or biologically active substances possiblypresent in the composition b) of the multilayer composite material (CM)according to the present invention, can be medical extracts of a naturalor synthetic origin; drugs for topical use such as non-steroidalanti-inflammatory drugs (NSAIDs); various kinds of steroids;antibacterials/antibiotics, preferably silver sulfadiazine; cytostatics,preferably metallic silver; growth factors; fibrinolytic andantiedematous substances; proteolytic enzymes, preferably collagenases;hyaluronidase; anticoagulants.

The composition b) preferably comprises:

-   -   sodium salt of hyaluronic acid (HA), prepared from hyaluronic        acid having a weight average molecular weight ranging from 150        to 2,000 kDa, preferably from 150 10 to 500 kDa, even more        preferably from 150 to 250 kDa, as such, or in association with        another polysaccharide, preferably with chitosan derivatized        with lactose,    -   possibly a protein selected from silk fibroin and collagen,    -   possibly pharmacologically and/or biologically active        substances, preferably in combination with silver sulfadiazine        or metallic silver.

In a different embodiment of the present invention, the composition b)preferably comprises:

-   -   sodium salt of hyaluronic acid (HA), prepared from hyaluronic        acid having a weight average molecular weight ranging from 150        to 250 kDa, or hybrid complexes of hyaluronic acid having a high        and low molecular weight or a mixture thereof,    -   possibly a protein selected from silk fibroin and collagen,    -   possibly in association with pharmacologically and/or        biologically active substances, preferably in combination with        silver sulfadiazine or metallic silver.

A preferred medical extract of a natural origin is the extract ofTriticum vulgare, which is used in the composite multilayer material ofthe present invention and can be obtained by the methods commonly usedfor the extraction of active ingredients from plant raw materials andknown to persons skilled in the field.

The composite multilayer material of the present invention can, as anon-limiting example, comprise a composition comprising aqueous extractof Triticum vulgare, for example having a dry residue of about 200mg/100 ml, and optionally also comprising phenoxyethanol.

In the context of the present invention, “hyaluronic acid” (hereinafteralso “HA”) refers to a hetero-polysaccharide composed of alternatingresidues of D-glucuronic acid and N-acetyl-D-glucosamine, with a linearchain, with a molecular weight which can range from 400 to 3×10⁶ Dalton(Da), depending on the extraction source or preparation method used. HAis ubiquitously present and plays an important role in the biologicalorganism, especially as a mechanical support of the cells of manytissues such as the skin, tendons, muscles and cartilage.

It is also known that HA, through its membrane receptor CD44, modulatesmany different processes relating to the physiology and biology of cellssuch as, for example, proliferation, migration, cell differentiation andangiogenesis, and carries out further important functions such as thehydration of tissues and the lubrication of the joints.

It has been shown that HA is determinant in the tissue repair processboth from the structural point of view (in the organization of theextracellular matrix and in the regulation of its hydration) and also asa stimulating substance of a wide range of processes in which itintervenes directly and indirectly (formation of coagulation, phagocyticactivity, fibroblast proliferation, neovascularization,re-epithelialization, etc.) (Weigel P. et al., J Theoretical Biol, 1986:219-234; Abatangelo G. et al., J Surg Res, 1983, 35: 410-416; Goa K. etal., Drugs, 1994, 47: 536-566). The combination of these widelyrecognized properties has long been exploited in the preparation ofdressings used in the treatment of wounds, ulcers and skin lesions ofvarious origins, superficial or deep.

The HA used in the present invention can derive from any source, forexample, from rooster combs (EP138572), from fermentation (fromStreptococcus equi or zooepidemicus, EP0716688), or from biosynthesis(from Bacillus, EP2614088 A1, EP2614087 A1), and be purified accordingto different techniques (W02018/020458 A1, IT102017000081449). Theweight average molecular weight (MW) of the polymer for the applicationsdescribed herein can range from 400 to 3×10⁶ Da, preferably from 100,000to 2×10⁶ Da, more preferably from 150 to 2,000 kDa, even more preferablyfrom 150 to 500 kDa or from 150 to 250 kDa. For the sake of brevity, thelatter is generally referred to as “HA with average weight MW 200 kDa”.

In the context of the present invention, average molecular weight of HArefers to the weight average MW calculated with the “intrinsicviscosity” method (Terbojevich et al., Carbohydr Res, 1986, 363-377).

It is understood that the MW is that of the starting hyaluronic acidbefore preparing the finished product, i.e. at the moment of preparationof the impregnating composition.

In a preferred embodiment of the present invention, in the multilayercomposite material (CM), the hyaluronic acid in the composition b) hasan average molecular weight ranging from 150 kDa to 500 kDa, morepreferably from 150 to 250 kDa. The inventors have surprisingly foundthat the multilayer composite material (CM) according to the presentinvention allows a dressing of wounds and lesions of the skin ingeneral, which is effective, easy to use and practically free of thedisadvantages of the known dressings described above.

The multilayer composite material (CM) according to the presentinvention comprises a three-dimensional matrix a), which is composed ofat least two layers (i. and ii) of polyester fabric, preferablypolyethylene terephthalate (PET), preferably monofilament, held togetherby two or more joints or welding points, carried out, for example, byultrasound, at regular intervals. The structure of the multilayercomposite material (CM) according to the present invention is similar tothat of a quilted fabric, in which the two layers i. and ii. aresuperimposed through the most extended surfaces, like the pages of abook. A cage is then formed which entraps the healing substance inside,specifically HA, and which releases it gradually, homogeneously,continuously and constantly through the pores of the fabric, whereinfabric specifically refers to a thin and flexible product with a flatsurface, produced by an interweaving of threads perpendicular to eachother.

The weave, that is the combination of weft and warp, of the single layerof fabric is thick, and consequently the pores between one mesh and theother have very reduced dimensions. As known to skilled persons in thefield, the weave of a fabric is modulated, with the same thread size, byvarying the number of meshes which, horizontally and vertically, withrespect to a reference unit, constitute the fabric. In this specificcase, the number of meshes in 1 cm of fabric varies, vertically, from 10to 15, and preferably from 11 to 12, and horizontally, ranges from 10 to17, and preferably from 11 to 15. This thick weave and, therefore,extremely small pores, on the one hand ensure flexibility of thematerial and, on the other, prevent the fabric itself from integrating,even minimally, with the wound on which it is applied.

It should be pointed out that the layers of fabric i. and ii. to becoupled to constitute the three-dimensional matrix a) must be identical,i.e. having the same number of meshes horizontally and verticallyrespectively.

Furthermore, the matrix a) comprising, or consisting of, polyesterfabric, preferably PET, preferably monofilament, does not release fibersin biological tissues, therefore the risk of contamination and thepresence of gauze residues in the biological tissues after dressing isminimized.

It is understood that the multilayer composite material (CM) accordingto the present invention can also comprise other layers of fabric orother components in addition to the layers i. and ii., as describedabove.

The matrix a) obtained by welding at least two layers of fabriccomprising polyester, preferably PET, as described above, can beimpregnated with an aqueous base composition comprising at leasthyaluronic acid and one or more excipients suitable for pharmaceuticaluse. Said composition fills, at least in part, the space S between thetwo layers i. and ii., producing the multilayer composite material (CM)according to the invention. Said composition is preferably distributeduniformly throughout the space S defined by the two layers i. and ii. ofthe matrix a). Said composition can also be present, at least in part,on the surfaces of the layers i. and ii. that are external to theintermediate space S.

In other words, the multilayer composite material (CM) according to thepresent invention comprises a three-dimensional matrix that forms a cagewhich entraps the HA composition, releasing it progressively.

Non-limiting examples of the excipients which can be used in saidcomposition comprising hyaluronic acid are all excipients suitable forthe production of pharmaceutical formulations, including, withoutlimitation, polyethylene glycol (PEG) and polyols, such as glycerol.

There are numerous advantages of the present invention. The multilayercomposite material (CM) according to the present invention has, amongothers, the following advantages.

The multi-layer composite material (CM) is soft, flexible, can be easilycut, for example with scissors, and is therefore perfectly adaptable tothe bed of the wound.

The multilayer composite material (CM) allows uniform and homogeneousdistribution of the HA composition, and therefore a uniform andhomogeneous release of the same.

The multilayer composite material (CM) remains firmly fixed on the woundeven without any adhesive, even if the presence of adhesive layers isnot excluded from the scope of the present invention.

The multilayer composite material (CM) can be easily and painlesslyremoved, as the very small pores due to the thick weave and hydrophobicnature of the polyester, also prevent surface integration with theeschar, especially in the case of exuding wounds, and therefore newlyformed scarring tissue is not torn away from the wound at the moment ofremoval.

The multilayer composite material (CM) does not release debris/residues,such as fiber fragments, in the wound.

The multilayer composite material (CM) can be sterilized with gamma orbeta rays.

For all these characteristics, the multilayer composite material (CM)according to the present invention can be replaced every 24, 48 or 72hours, instead of every 8 hours as necessary for wound-dressing productscurrently on the market.

When the composition b) comprises only synthetic polymers such aspolyurethanes, the multilayer composite material (CM) can however beparticularly advantageous, as it can absorb the exudates with particulareffectiveness.

In a preferred embodiment, in the multilayer composite material (CM)according to the present invention, the composition b) further comprisesmetallic silver or at least a silver salt, preferably silversulfadiazine.

In the context of the present invention, the term “silver sulfadiazine”refers to the monoargentic salt (Ag (I)) of sulfadiazine, CAS No.22199-08-2. It is intended that silver sulfadiazine derivatives andcomplexes can also form part of the composition of the invention.

In the context of the present invention, the term “metallic silver”refers to all forms of silver in oxidation state 0 known to skilledpersons in the field of pharmaceutical formulations, including, withoutlimitation, micronized and colloidal silver.

In a preferred embodiment of the invention, in the multilayer compositematerial (CM), the fabric of the layer i. and/or of the layer ii. is amonofilament fabric.

In a preferred embodiment of the invention, in the multilayer compositematerial (CM), the fabric of the layer i. and/or of the layer ii.comprises, or consists of, polyester, more preferably at least one ofpolyethylene terephthalate (PET), a natural polyester, such as apolyhydroxyalkanoate (PHA), e.g. polyhydroxybutyrate (PHB), even morepreferably PET (polyethylene terephthalate).

In a preferred embodiment of the invention, in the multilayer compositematerial (CM), the fabric of the layer i. and/or of the layer ii.contains from 10 to 15 meshes, preferably from 11 to 12, vertically andfrom 10 to 17 mesh, preferably from 11 to 15, horizontally.

In a preferred embodiment of the invention, the multilayer compositematerial (CM) has a thickness ranging from 0.2 to 2 mm, even morepreferably from 0.5 to 1 mm. The dimensions of the dressing are variabledepending on the type of wound or injury to be treated. As anon-limiting example, the multilayer composite material (CM) can havedimensions varying from 5×5 cm. to 30×30 cm, preferably 10×10 cm.

The welding between the two layers i. and ii, and, if present, betweenother layers of the three-dimensional matrix a) can be carried out, as anon-limiting example, by means of ultrasounds. Said welding ispreferably effected so as to produce punching at a distance that canvary from 10 to 20 mm, more preferably from 15 to 16 mm, with a regularor irregular pattern.

In the multilayer composite material (CM) according to the presentinvention, the concentration of HA in the impregnation composition,expressed as w/w with respect to the impregnation composition, rangesfrom 0.01 to 1%, preferably from 0.02 to 0.5%, even more preferably from0.03% to 0.2%.

The amount of HA in the final dressing can vary according to the size ofthe dressing. In a dressing having dimensions of 10×0 cm, for example,the HA varies from 0.4 to 40 mg, preferably from 0.8 to 20 mg, even morepreferably from 1.2 to 8 mg.

The concentration of silver sulfadiazine, expressed as weight/weightwith respect to the impregnating composition, preferably ranges from 0.1to 3%, and is more preferably equal to 1%.

In addition to HA and, when present, silver sulfadiazine, at theconcentration ranges mentioned above, the impregnating composition canalso comprise as excipients, glycerol in variable amounts ranging from10 to 30%, preferably equal to 25%, PEG 4000 in variable amounts rangingfrom 30 to 70%, preferably equal to 50%, and water for the remainingpart; the quantities are expressed as weight with respect to the weightof the final composition.

In an embodiment, the present invention also relates to a dressingconsisting of or comprising

-   a) a three-dimensional matrix comprising at least a first layer i.    end a second layer ii. of fabric including, or consisting of a PET    fiber, wherein said first layer i. and said second layer ii. are    superimposed and welded together in at least two different and    separated points, so as to define a space S between the two    layers i. and ii. and-   b) a composition comprising, or consisting of hyaluronic acid, and    at least one excipient suitable for pharmaceutical use, and possibly    further comprising silver sulfadiazine, wherein said composition b)    is contained in at least a part of said space S between the    layers i. and ii.    wherein said dressing has dimension of about 9×9 cm and contains    4.1±0.5 g of composition b) prepared starting from hyaluronic acid    having a weight average molecular weight ranging from 150 to 250    kDa, the total content of HA in the dressing being equal to 2 mg and    the total content of silver sulfadiazine in the dressing, when    present, being equal to 40 mg.

In an embodiment, the present invention also relates to a dressingconsisting of or comprising the multilayer composite material (CM),wherein said dressing has dimensions of about 9×9 cm and contains4.1±0.5 g of composition b), prepared starting from hyaluronic acidhaving a weight average molecular weight ranging from 150 to 250 kDa,the total content of HA in the dressing being equal to 2 mg.

The silver sulfadiazine, when present, is preferably 1%, therefore eachdressing contains about 40 mg of silver sulfadiazine. In a preferredembodiment, the fabric of the layer i. and ii. consists of monofilamentpolyethylene terephthalate and preferably contains from 11 to 12 meshesper centimetre vertically and preferably from 11 to 15 meshes percentimetre horizontally. The layers of fabric forming thethree-dimensional matrix a) are welded by means of ultrasounds withpunching at a distance ranging from 15 to 16 mm.

An object of the present invention relates to the multilayer compositematerial (CM) as described above, or a dressing comprising saidcomposite material (CM), for the use in the treatment of a wound,abrasion, cut, ulcer, sore, burn, lesion or laceration of the skin in asubject, wherein said treatment includes the application of saidmultilayer composite material on the surface of the wound, abrasion,cut, lesion or laceration of the skin and, possibly, of the underlyingtissues.

In a preferred embodiment, in the multilayer composite material (CM) forthe use described above, the composition b) also comprises silversulfadiazine.

An object of the present invention also relates to a method for thetreatment of a wound, abrasion, cut, ulcer, sore, burn, lesion orlaceration of the skin in a subject which comprises the application ofthe multilayer composite material (CM) as described above, or theapplication of a dressing comprising said composite material (CM) on thepart of the body of the subject affected by the wound, abrasion, cut,lesion or laceration of the skin.

1. A multilayer composite material (CM) comprising at least: a) athree-dimensional matrix comprising at least a first layer and a secondlayer of a fabric comprising, or consisting of a polyester fiber,wherein said first layer and said second layer are superimposed andwelded together in at least two distinct and separate points, so as todefine a space S between the first layer and the second layer; and b) acomposition comprising, or consisting of at least one natural,semi-synthetic or synthetic polymer, possibly mixed together; possiblyone or more pharmacologically and/or biologically active substance, andat least one excipient suitable for pharmaceutical use, wherein saidcomposition b) is contained in at least a part of said space S includedbetween the first layer and the second layer.
 2. The multilayercomposite material (CM) according to claim 1, wherein the natural orsemi-synthetic polymers are polysaccharides, proteins, polypeptides orpolynucleotides; the synthetic polymers are polyacrylic acid;polyacrylates; polyaspartamide; poly(ethyleneglycol) (PEG);polyvinyl-pyrrolidone; polylactic acid, poly(lactic-glycolic) acid;polyanhydrides; polyorthoesters; polyphosphoesters; polyphosphazenes;polycyanoacrylic derivatives; poly(N-isopropylacrylamide); polylysine;polyhistidine; polyamidoamine; polyglutamic acid; polysiloxanes;polyurethanes; polytetrafluoroethylene (PTFE).
 3. The multilayercomposite material (CM) according to claim 2, wherein thepolysaccharides are selected from: glycosaminoglycans; chitin, chitosanand its derivatives; pectin or pectinic acid; galactans; alginates;glucans; natural gums, xanthan, gellan; fructans; polymannans; andcarrageenan.
 4. The multilayer composite material (CM) according toclaim 2, wherein the proteins or polypeptides are: collagen,co-precipitates of collagen and glycosaminoglycans, gelatin, elastin,fibrin, fibrinogen, keratin, silk, silk fibroin alone or in combinationwith sericin, or silk sericin.
 5. The multilayer composite material (CM)according to claim 1, wherein the pharmacologically and/or biologicallyactive substances are natural extracts of a natural or synthetic origin;drugs for topical use; steroids; antibacterials/antibiotics;cytostatics; growth factors; fibrinolytic and antiedematous substances;proteolytic enzymes; hyaluronidase; anticoagulants.
 6. The multilayercomposite material (CM) according to claim 1, wherein the composition b)comprises: sodium salt of hyaluronic acid (HA), prepared starting fromhyaluronic acid having a weight average molecular weight ranging from150 to 2,000 kDa optionally in association with another polysaccharide,optionally a protein selected from silk fibroin and collagen, andoptionally pharmacologically and/or biologically active substances. 7.The multilayer composite material (CM) according to claim 1, wherein thecomposition b) comprises: sodium salt of hyaluronic acid (HA), preparedfrom hyaluronic acid having a weight average molecular weight rangingfrom 150 to 250 kDa, or hybrid complexes of high- orlow-molecular-weight hyaluronic acid or a mixture thereof, optionally aprotein selected from silk fibroin and collagen, and optionallyassociated with pharmacologically and/or biologically active substances.8. The multilayer composite material (CM) according to claim 1, whereinthe composition b) comprises metallic silver or at least one silver saltor complex.
 9. The multilayer composite material (CM) according to claim1, wherein the fabric of the first layer and/or of the second layer is amonofilament fabric.
 10. The multilayer composite material (CM)according to claim 1, wherein the fabric of the first layer and/or ofthe second layer comprises or consists of at least one of polyethyleneterephthalate (PET), and/or a natural polyester.
 11. The multilayercomposite material (CM) according to claim 1, wherein the fabric of thefirst layer and/or of the second layer contains from 10 to 15 meshes,vertically, and from 10 to 17 meshes horizontally.
 12. The multilayercomposite material (CM) according to claim 1, wherein the fabric of thefirst layer and/or of the second layer are welded by means of pointsobtained by welding so as to obtain points at a distance ranging from 10to 20 mm from one another.
 13. The multilayer composite material (CM)according to claim 1, or a dressing comprising said multilayer compositematerial (CM) for the use in the treatment of a wound, abrasion, cut,ulcer, sore, burn, lesion or laceration of the skin in a subject,wherein said treatment comprises the application of said multilayercomposite material on the surface of the wound, abrasion, cut, ulcer,sore, burn, lesion or laceration of the skin and, optionally, of theunderlying tissues.
 14. A dressing consisting of or comprising: a) athree-dimensional matrix comprising at least a first layer and a secondlayer of a fabric comprising a polyethylene terephthalate (PET) fiber,wherein said first layer and said second layer are superimposed andwelded together in at least two distinct and separate points, so as todefine a space S between the first layer and the second layer; and b) acomposition comprising hyaluronic acid and at least one excipientsuitable for pharmaceutical use, and possibly further including silversulfadiazine, wherein said composition b) is contained in at least apart of the space S between the first layer and the second layer;wherein said dressing has dimensions of about 9×9 cm and contains4.1±0.5 g of composition b) prepared starting from hyaluronic acidhaving a weight average molecular weight ranging from 150 to 250 kDa,wherein the total content of hyaluronic acid (HA) in the dressing isequal to 2 mg and the total content of silver sulfadiazine in thedressing, when present, is equal to 40 mg.
 15. The multilayer compositematerial (CM) according to claim 2, wherein the polyacrylate is pHEMA[poly-2-hydroxyethyl-methacrylate]; the poly(lactic-glycolic) acid ispolylactic-co-glycolic acid (PLGA), polyglycolic acid (PGA), orpolycaprolactone.
 16. The multilayer composite material (CM) accordingto claim 1, wherein the synthetic polymers are polyurethanes.
 17. Themultilayer composite material (CM) according to claim 3, wherein theglycosaminoglycans are selected from hyaluronic acid and/or derivativesthereof selected from salts, esters, amides and sulfated hyaluronicacid; hybrid complexes of high- and low-molecular-weight hyaluronicacid; chondroitin, chondroitin sulfate, dermatan sulfate,keratansulfate, heparan sulfate, heparin and heparinoids; chitosan ischitosan derivatized with lactose; galactans are agar or agarose;alginates are alginic acid; glucans are selected from dextran, dextrin,trehalose, maltose, starch, cellulose and its derivatives; and fructansare inulin.
 18. The multilayer composite material (CM) according toclaim 5, wherein the drugs for topical use are NSAIDs;antibacterials/antibiotics are silver sulfadiazine; cytostatics aremetallic silver; and proteolytic enzymes are collagenases.
 19. Themultilayer composite material (CM) according to claim 6, wherein thesodium salt of hyaluronic acid (HA) is prepared starting from hyaluronicacid having a weight average molecular weight ranging from 150 to 500kDa.
 20. The multilayer composite material (CM) according to claim 6,wherein the sodium salt of hyaluronic acid (HA) is prepared startingfrom hyaluronic acid having a weight average molecular weight rangingfrom 150 to 250 kD.
 21. The multilayer composite material (CM) accordingto claim 6, wherein the optionally pharmacologically and/or biologicallyactive substances is in combination with silver sulfadiazine.
 22. Themultilayer composite material (CM) according to claim 8, wherein thecomposition b) comprises silver sulfadiazine.
 23. The dressing accordingto claim 14, wherein the composition b) further comprises at least onenatural or semi-synthetic polymers selected from polysaccharides,proteins, polypeptides or polynucleotides; the synthetic polymers arepolyacrylic acid; polyacrylates; polyaspartamide; poly(ethyleneglycol)(PEG); polyvinyl-pyrrolidone; polylactic acid, poly(lactic-glycolic)acid; polyanhydrides; polyorthoesters; polyphosphoesters;polyphosphazenes; polycyanoacrylic derivatives;poly(N-isopropylacrylamide); polylysine; polyhistidine; polyamidoamine;polyglutamic acid; polysiloxanes; polyurethanes; andpolytetrafluoroethylene (PTFE).
 24. The dressing according to claim 23,wherein the polysaccharides are selected from: glycosaminoglycans;chitin, chitosan and its derivatives; pectin or pectinic acid;galactans; alginates; glucans; natural gums, xanthan, gellan; fructans;polymannans; and carrageenan.
 25. The dressing according to claim 23,wherein the proteins or polypeptides are: collagen, co-precipitates ofcollagen and glycosaminoglycans, gelatin, elastin, fibrin, fibrinogen,keratin, silk, silk fibroin alone or in combination with sericin, orsilk sericin.
 26. The dressing according to claim 14, wherein thecomposition b) further comprises one or more pharmacologically and/orbiologically active substances selected form natural extracts of anatural or synthetic origin; drugs for topical use; steroids;antibacterials/antibiotics; cytostatics; growth factors; fibrinolyticand antiedematous substances; proteolytic enzymes; hyaluronidase; andanticoagulants.
 27. The dressing according to claim 14, wherein thecomposition b) further comprises at least one of: the sodium salt ofhyaluronic acid (HA) in association with another polysaccharide, aprotein selected from silk fibroin and collagen, pharmacologicallyand/or biologically active substances.
 28. The dressing according toclaim 14, wherein the composition b) comprises metallic silver or atleast one silver salt or complex.
 29. The dressing according to claim14, wherein the fabric of the first layer and/or of the second layer isa monofilament fabric.
 30. The dressing according to claim 14, whereinthe fabric of the second layer further comprises a natural polyester.31. The dressing according to claim 14, wherein the first layercomprises or consists of at least one of polyethylene terephthalate(PET), and/or a natural polyester.
 32. The dressing according to claim14, wherein the fabric of the first layer and/or of the second layercontains from 10 to 15 meshes, vertically, and from 10 to 17 mesheshorizontally.
 33. The dressing according to claim 14, wherein the fabricof the first layer and/or of the second layer are welded by means ofpoints obtained by welding so as to obtain points at a distance rangingfrom 10 to 20 mm from one another.
 34. A method of treating a wound,abrasion, cut, ulcer, sore, burn, lesion or laceration of the skin in asubject, which comprises applying the dressing according to claim 14 tothe surface of the wound, abrasion, cut, ulcer, sore, burn, lesion orlaceration of the skin and, optionally, of the underlying tissues. 35.The dressing according to claim 23, wherein the polyacrylate is pHEMA[poly-2-hydroxyethyl-methacrylate]; the poly(lactic-glycolic) acid ispolylactic-co-glycolic acid (PLGA), polyglycolic acid (PGA), orpolycaprolactone.
 36. The dressing according to claim 24, wherein theglycosaminoglycans are selected from hyaluronic acid and/or derivativesthereof selected from salts, esters, amides and sulfated hyaluronicacid; hybrid complexes of high- and low-molecular-weight hyaluronicacid; chondroitin, chondroitin sulfate, dermatan sulfate,keratansulfate, heparan sulfate, heparin and heparinoids; chitosan ischitosan derivatized with lactose; galactans are agar or agarose;alginates are alginic acid; glucans are selected from dextran, dextrin,trehalose, maltose, starch, cellulose and its derivatives; and fructansare inulin.
 37. The dressing according to claim 26, wherein the drugsfor topical use are NSAIDs; antibacterials/antibiotics are silversulfadiazine; cytostatics are metallic silver; and proteolytic enzymesare collagenases.
 38. The dressing according to claim 27, wherein theoptionally pharmacologically and/or biologically active substances is incombination with silver sulfadiazine.
 39. The dressing according toclaim 28, wherein the composition b) comprises silver sulfadiazine.